Recent research suggests that there can be genetic causes of Parkinson's disease. In several forms of the disease, these genetic disturbances appear to compromise function of the cells' energy factories, called "mitochondria," which are present in large numbers in all cells.
Since the most significant brain change in Parkinson's disease is the progressive loss of nerve cells making the signaling substance dopamine, we have modeled impaired function of mitochondria in dopamine nerve cells. By generating mice in which the mitochondria in dopamine nerve cells lose the ability to use oxygen to make energetic molecules (ATP), we have obtained animals that develop Parkinson-like symptoms and Parkinson-like changes in the brain. In this genetic model, there is no need to administer toxic substances; disease development is solely due to the genetic modification (removal of a gene called TFAM in dopamine neurons).
Support from The Michael J. Fox Foundation will allow us to study in detail the mechanisms of slow nerve cell death in this model. One interesting aspect is that the dying nerve cells develop protein aggregates that bear similarities to the Lewy bodies (protein clumps) in nerve cells that are the pathological hallmark of Parkinson's disease. The development of protein aggregates will be analyzed in the mice and may shed light on the genesis of Lewy bodies.
Progress Report
Drs. Olson and Larsson confirmed selective dopaminergic degeneration in the mice, and further characterized the time course of changes and the composition of the protein aggregates. This work was supplemented by MJFF to further characterize the model and test neurotrophic factors to determine the model's predictive value.
Final Outcome
Dr. Olson and his team tested the effects of intrastriatal viral delivery of the neurotrophic factor GDNF in the mice and observed a slight behavioral improvement. This improvement appeared not to be paralleled by effects on nigrostriatal dopamine neurons as measured by TH-immunoreactivity, but further studies of this and of dopamine levels are needed. Infusion of GDNF protein also appeared to improve behavioral effects.